Sweetener compositions and methods of making them

ABSTRACT

The present invention provides compositions comprising sucralose and 4-amino-5,6-dimethylthieno [2,3-d]pyrimidine-2(1H)-one or salts, solvates, and/or esters thereof and methods of making the compositions by spray drying. The present invention also provides ingestible compositions comprising compositions of the present invention and methods of making such foods. The present invention also includes a process of preparing 2-amino-thiophene derivatives, which are key intermediates for preparing 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.61/026,640, filed Feb. 6, 2008 and entitled “Sweetener Compositions andMethods of Making Them”, the content of which is herein incorporated byreference in its entirety for all purposes. This application is alsorelated to U.S. patent application Ser. No. 11/760,592, filed Jun. 8,2007 and entitled “Modulation of Chemosensory Receptors and LigandsAssociated Therewith”; U.S. patent application Ser. No. 11/836,074,filed Aug. 8, 2007 and entitled “Modulation of Chemosensory Receptorsand Ligands Associated Therewith”; U.S. patent application Ser. No.61/027,410, filed Feb. 8, 2008 and entitled “Modulation of ChemosensoryReceptors and Ligands Associated Therewith”; and InternationalApplication No. PCT/US2008/065650, filed Jun. 3, 2008 and entitled“Modulation of Chemosensory Receptors and Ligands Associated Therewith”.The content of these applications are herein incorporated by referencein their entirety for all purposes.

FIELD OF THE INVENTION

This invention relates to compositions comprising the combination ofsucralose with 4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2(1H)-one, orsalts, solvates and/or esters thereof, methods of making suchcompositions, and methods of making, e.g. ingestible products with suchcompositions. This invention also relates to processes of preparing2-amino-thiophene compounds.

BACKGROUND OF THE INVENTION

Obesity, diabetes, and cardiovascular disease are health concerns on therise globally, but are growing at alarming rates in the United States.Sugar and calories are key components that can be limited to render apositive nutritional effect on health. High-intensity sweeteners canprovide the sweetness of sugar, with various taste qualities. Becausethey are many times sweeter than sugar, much less of the sweetener isrequired to replace the sugar.

High-intensity sweeteners have a wide range of chemically distinctstructures and hence possess varying properties, such as, withoutlimitation, odor, flavor, mouthfeel, and aftertaste. These properties,particularly flavor and aftertaste, are well known to vary over the timeof tasting, such that each temporal profile is sweetener-specific(Tunaley, A., “Perceptual Characteristics of Sweeteners”, Progress inSweeteners, T. H. Grenby, Ed. Elsevier Applied Science, 1989)).

Sweeteners such as saccharin and6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt(acesulfame potassium) are commonly characterized as having bitterand/or metallic aftertastes. Products prepared with 2,4-dihydroxybenzoicacid are claimed to display reduced undesirable aftertastes associatedwith sweeteners, and do so at concentrations below those concentrationsat which their own tastes are perceptible. In contrast, somehigh-intensity sweeteners, notably sucralose(1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galacto-pyranoside) and aspartame (N-L-α-aspartyl-L-phenylalaninemethyl ester), display clean sweet tastes very similar to that of sugar(S. G. Wiet and G. A. Miller, Food Chemistry, 58(4):305-311 (1997)). Inother words, these compounds are not characterized as having bitter ormetallic aftertastes.

However, high intensity sweeteners such as sucralose and aspartame arereported to have sweetness delivery problems, i.e., delayed onset andlingering of sweetness (S. G. Wiet, et al., J. Food Sci., 58(3):599-602,666 (1993)).

Hence, there is a need for compositions containing high intensitysweeteners with improved taste and delivery characteristics. In additionthere is a need for foods containing high intensity sweeteners with suchdesirable characteristics.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to compositioncomprising a plurality of solid particles, each particle comprisingsucralose and 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one orsalts, solvates, and/or esters thereof.

In another embodiment, the present invention is directed to acomposition comprising a plurality of solid particles, each particlecomprising sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, prepared by spray drying a solution ordispersion comprising the sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof.

In yet another embodiment the present invention is directed to aningestible product comprising sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, or salts,solvates, and/or esters thereof.

In still another embodiment, the present invention is directed to amethod of making a composition comprising solid particles, each particlecomprising sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, or salts,solvates, and/or esters thereof, said method comprising spray drying asolution or dispersion comprising the sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof.

In yet still another embodiment, the present invention is directed to amethod of making an ingestible product, comprising combining sucraloseand 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-thione, or salts,solvates, and/or esters thereof, with one or more edible ingredients.

In yet still another embodiment, the present invention is directed to amethod of improving the sweetness delivery profile of asucralose-containing ingestible composition, comprising incorporatinginto said sucralose-comprising ingestible composition4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, wherein4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one:sucralose weightratio ranges from about 1:2 to about 1:50.

In yet still another embodiment, the present invention is directed to aprocess of preparing a compound having structural Formula (a):

The process comprises mixing a compound having structural Formula (b):

with a compound having structural Formula (c):

in the presence of an organic amine at a temperature of about 0° C. orbelow to obtain a reaction mixture; maintaining the reaction mixture ata temperature of about 0° C. or below for about 30 to about 90 minutes;concentrating the reaction mixture to obtain a slurry; and filtering theslurry to obtain the compound having structural Formula (a) as solidparticles; wherein: R¹ is hydrogen, alkyl, heteroalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl; R² is hydrogen, alkyl,heteroalkyl, alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;or alternatively, R¹ and R², together with the atoms to which they areattached, form a carbocyclic ring or heterocyclic ring; X is CN or—C(O)R³; R³ is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR⁴,or N(R⁴)₂; and each R⁴ is independently hydrogen, alkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited in the present specification are incorporated byreference in their entirety for all purposes.

The compositions of the present invention comprise sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof. In one embodiment, the compositions ofthe present invention comprise a plurality of particles, e.g., in theform of a powder, wherein each of the particles comprises sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof.

As used herein, 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onemeans the compound of formula (I):

or salts, solvates, and/or esters thereof.

Compounds of formula (I) also includes tautomeric forms, includingsalts, solvates, and/or esters of the tautomeric forms. For example, atautomeric form of formula (I) includes compounds of formula (Ia):

Salt(s) of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one refersto the product formed by the reaction of a suitable inorganic or organicacid with 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one (as the“free base”). Suitable acids include those having sufficient acidity toform a stable salt, for example acids with low toxicity, such as thesalts approved for use in humans or animals. Non-limiting examples ofacids which may be used to form salts of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one include inorganicacids, e.g., HF, HCl, HBr, HI, H₂SO₄, H₃PO₄; non-limiting examples oforganic acids include organic sulfonic acids, such as C₆₋₁₆ arylsulfonic acids, C₆₋₁₆ heteroaryl sulfonic acids or C₁₋₁₆ alkyl sulfonicacids—e.g., phenyl, a-naphthyl, β-naphthyl, (S)-camphor, methyl, ethyl,n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexylsulfonic acids; non-limiting examples of organic acids includescarboxylic acids such as C₁₋₁₆ alkyl, C₆₋₁₆ aryl carboxylic acids andC₄₋₁₆ heteroaryl carboxylic acids, e.g., acetic, glycolic, lactic,pyruvic, malonic, glutaric, tartaric, citric, furmaric, succinic, malic,maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic and 2-phenoxybenzoic acids; non-limiting examples of organicacids include amino acids, e.g. the naturally-occurring amino acids,lysine, arginine, glutamic acid, glycine, serine, threonine, alanine,isoleucine, leucine, etc. Other suitable salts can be found in, e.g., S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19 (herein incorporatedby reference for all purposes). In one embodiment, salts of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one refers to saltswhich are biologically compatible or pharmaceutically acceptable ornon-toxic, particularly for mammalian cells. In a particular embodiment,a suitable salt is 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride. The salts of invention compounds may be crystalline oramorphous, or mixtures of different crystalline forms and/or mixtures ofcrystalline and amorphous forms.

Salt(s) of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one alsorefer to the product formed by the reaction of a suitable base with thetautomer of formula (1a). Non limiting examples of basic salts include,alkali metal salts such as the sodium and potassium salt; alkaline earthmetal salts such as magnesium or calcium salts; transition metal saltssuch as ferric salts, etc.

Esters of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one include,e.g. esters formed by reacting the phenolic hydroxyl group of thetautomeric form (Ia) with an acid. For example, (1) carboxylic acidesters obtained by esterification of the phenolic hydroxyl group of atautomer of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, inwhich the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Solvates of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one referto solid forms of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onein which one or more solvent molecules, for example water, are complexedto the 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one.

The compositions of the present invention can consist only of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(II)-one or salts,solvates, and/or esters thereof, and sucralose, or can includeadditional ingredients, e.g., one or more additional sweeteners.

In other embodiments, the sucralose can be admixed with the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof using conventional techniques such asdry blending, blending solutions/suspensions of the sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, etc.

“Sweeteners” include, but are not limited to the common saccharidesweeteners, e.g., sucrose, fructose, glucose, and sweetener compositionscomprising natural sugars, such as corn syrup (including high fructosecorm syrup) or other syrups or sweetener concentrates derived fromnatural fruit and vegetable sources, semi-synthetic “sugar alcohol”sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol,xylitol, maltodextrin, and the like, and artificial sweeteners such asaspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame.Sweeteners also include cyclamic acid, mogroside, tagatose, maltose,galactose, mannose, sucrose, fructose, lactose, neotame and otheraspartame derivatives, glucose, D-tryptophan, glycine, maltitol,lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starchhydrolyzate (HSH), stevioside, rebaudioside A and other sweetStevia-based glycosides, carrelame and other guanidine-based sweeteners,etc. The term “sweeteners” also includes combinations of sweeteners asdisclosed herein.

The compositions of the present invention provide an improved “sweetnessdelivery profile” for compositions (e.g., ingestible compositions)sweetened with sucralose. The compositions of the present inventionprovide a shorter sweetness onset and a shorter sweetness lingeringperiod compared to conventional compositions with are sweetened withsucralose only, and do not contain the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof of the compositions of the presentinvention.

According to the present invention, “sweetness delivery profile” refersto a distinguishing characteristic of a sweetener which includes boththe time period preceding sweetness onset (“onset period”), and the timeperiod during which sweetness lingers (“lingering period”).

According to the present invention, an “ingestible composition” includesany substance intended for oral consumption either alone or togetherwith another substance. The ingestible composition includes both “foods”and “non-edible products”. For example, the ingestible compositionincludes comestible compositions/products and medicinalcompositions/products.

“Food” herein means any edible product intended for consumption byhumans or animals, including solids, semi-solids, or liquids (e.g.,beverages). The term “food” and the term “food and beverage” are hereinused interchangeably.

A variety of classes, subclasses and species of foods are known.Examples of food and beverage products or formulations include, but arenot limited to sweet coatings, frostings, or glazes for comestibleproducts or any entity included in the Soup category, the DriedProcessed Food category, the Beverage category, the Ready Meal category,the Canned or Preserved Food category, the Frozen Processed Foodcategory, the Chilled Processed Food category, the Snack Food category,the Baked Goods category, the Confectionary category, the Dairy Productcategory, the Ice Cream category, the Meal Replacement category, thePasta and Noodle category, and the Sauces, Dressings, Condimentscategory, the Baby Food category, and/or the Spreads category.

In general, the Soup category refers to canned/preserved, dehydrated,instant, chilled, UHT and frozen soup. For the purpose of thisdefinition soup(s) means a food prepared from meat, poultry, fish,vegetables, grains, fruit and other ingredients, cooked in a liquidwhich may include visible pieces of some or all of these ingredients. Itmay be clear (as a broth) or thick (as a chowder), smooth, pureed orchunky, ready-to-serve, semi-condensed or condensed and may be servedhot or cold, as a first course or as the main course of a meal or as abetween meal snack (sipped like a beverage). Soup may be used as aningredient for preparing other meal components and may range from broths(consommé) to sauces (cream or cheese-based soups).

“Dehydrated and Culinary Food Category” usually means: (i) Cooking aidproducts such as: powders, granules, pastes, concentrated liquidproducts, including concentrated bouillon, bouillon and bouillon likeproducts in pressed cubes, tablets or powder or granulated form, whichare sold separately as a finished product or as an ingredient within aproduct, sauces and recipe mixes (regardless of technology); (ii) Mealsolutions products such as: dehydrated and freeze dried soups, includingdehydrated soup mixes, dehydrated instant soups, dehydratedready-to-cook soups, dehydrated or ambient preparations of ready-madedishes, meals and single serve entrees including pasta, potato and ricedishes; and (iii) Meal embellishment products such as: condiments,marinades, salad dressings, salad toppings, dips, breading, battermixes, shelf stable spreads, barbecue sauces, liquid recipe mixes,concentrates, sauces or sauce mixes, including recipe mixes for salad,sold as a finished product or as an ingredient within a product, whetherdehydrated, liquid or frozen.

The Beverage category usually means beverages, beverage mixes andconcentrates, including but not limited to, carbonated andnon-carbonated beverages, alcoholic and non-alcoholic beverages, readyto drink beverages, liquid concentrate formulations for preparingbeverages such as sodas, and dry powdered beverage precursor mixes. TheBeverage category also includes the alcoholic drinks, the soft drinks,sports drinks, isotonic beverages, and hot drinks. The alcoholic drinksinclude, but are not limited to beer, cider/perry, FABs, wine, andspirits. The soft drinks include, but are not limited to carbonates,such as colas and non-cola carbonates; fruit juice, such as juice,nectars, juice drinks and fruit flavored drinks; bottled water, whichincludes sparkling water, spring water and purified/table water;functional drinks, which can be carbonated or still and include sport,energy or elixir drinks; concentrates, such as liquid and powderconcentrates in ready to drink measure. The hot drinks include, but arenot limited to coffee, such as fresh, instant, and combined coffee; tea,such as black, green, white, oolong, and flavored tea; and other hotdrinks including flavor-, malt- or plant-based powders, granules, blocksor tablets mixed with milk or water.

The Snack Food category generally refers to any food that can be a lightinformal meal including, but not limited to Sweet and savory snacks andsnack bars. Examples of snack food include, but are not limited to fruitsnacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn,pretzels, nuts and other sweet and savory snacks. Examples of snack barsinclude, but are not limited to granola/muesli bars, breakfast bars,energy bars, fruit bars and other snack bars.

The Baked Goods category generally refers to any edible product theprocess of preparing which involves exposure to heat or excessivesunlight. Examples of baked goods include, but are not limited to bread,buns, cookies, muffins, cereal, toaster pastries, pastries, waffles,tortillas, biscuits, pies, bagels, tarts, quiches, cake, any bakedfoods, and any combination thereof.

The Ice Cream category generally refers to frozen dessert containingcream and sugar and flavoring. Examples of ice cream include, but arenot limited to: impulse ice cream; take-home ice cream; frozen yoghurtand artisanal ice cream; soy, oat, bean (e.g., red bean and mung bean),and rice-based ice creams.

The Confectionary category generally refers to edible product that issweet to the taste. Examples of confectionary include, but are notlimited to candies, gelatins, chocolate confectionery, sugarconfectionery, gum, and the likes and any combination products.

The Meal Replacement category generally refers to any food intended toreplace the normal meals, particularly for people having health orfitness concerns. Examples of meal replacement include, but are notlimited to slimming products and convalescence products.

The Ready Meal category generally refers to any food that can be servedas meal without extensive preparation or processing. The ready mealinclude products that have had recipe “skills” added to them by themanufacturer, resulting in a high degree of readiness, completion andconvenience. Examples of ready meal include, but are not limited tocanned/preserved, frozen, dried, chilled ready meals; dinner mixes;frozen pizza; chilled pizza; and prepared salads.

The Pasta and Noodle category includes any pastas and/or noodlesincluding, but not limited to canned, dried and chilled/fresh pasta; andplain, instant, chilled, frozen and snack noodles.

The Canned/Preserved Food category includes, but is not limited tocanned/preserved meat and meat products, fish/seafood, vegetables,tomatoes, beans, fruit, ready meals, soup, pasta, and othercanned/preserved foods.

The Frozen Processed Food category includes, but is not limited tofrozen processed red meat, processed poultry, processed fish/seafood,processed vegetables, meat substitutes, processed potatoes, bakeryproducts, desserts, ready meals, pizza, soup, noodles, and other frozenfood.

The Dried Processed Food category includes, but is not limited to rice,dessert mixes, dried ready meals, dehydrated soup, instant soup, driedpasta, plain noodles, and instant noodles.

The Chill Processed Food category includes, but is not limited tochilled processed meats, processed fish/seafood products, lunch kits,fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pastaand noodles.

The Sauces, Dressings and Condiments category includes, but is notlimited to tomato pastes and purees, bouillon/stock cubes, herbs andspices, monosodium glutamate (MSG), table sauces, soy based sauces,pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup,mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickledproducts, and other sauces, dressings and condiments.

The Baby Food category includes, but is not limited to milk- orsoybean-based formula; and prepared, dried and other baby food.

The Spreads category includes, but is not limited to jams and preserves,honey, chocolate spreads, nut based spreads, and yeast based spreads.

The Dairy Product category generally refers to edible product producedfrom mammal's milk. Examples of dairy product include, but are notlimited to drinking milk products, cheese, yoghurt and sour milk drinks,and other dairy products.

Exemplary foods include confectioneries, chocolate confectionery,tablets, countlines, bagged selflines/softlines, boxed assortments,standard boxed assortments, twist wrapped miniatures, seasonalchocolate, chocolate with toys, alfajores, other chocolateconfectionery, mints, standard mints, power mints, boiled sweets,pastilles, gums, jellies and chews, toffees, caramels and nougat,medicated confectionery, lollipops, liquorice, other sugarconfectionery, gum, chewing gum, sugarized gum, sugar-free gum,functional gum, bubble gum, cough drops, herbs, seeds, spices, bread,packaged/industrial bread, unpackaged/artisanal bread, pastries, cakes,packaged/industrial cakes, unpackaged/artisanal cakes, cookies,chocolate coated biscuits, sandwich biscuits, filled biscuits, savorybiscuits and crackers, bread substitutes, breakfast cereals, ready toeat cereals, family breakfast cereals, flakes, muesli, other cereals,children's breakfast cereals, hot cereals, ice cream, impulse ice cream,single portion dairy ice cream, single portion water ice cream,multi-pack dairy ice cream, multi-pack water ice cream, take-home icecream, take-home dairy ice cream, ice cream desserts, bulk ice cream,take-home water ice cream, frozen yoghurt, artisanal ice cream, dairyproducts, milk, fresh/pasteurized milk, full fat fresh/pasteurized milk,semi skimmed fresh/pasteurized milk, long-life/uht milk, full fat longlife/uht milk, semi skimmed long life/uht milk, fat-free long life/uhtmilk, goat milk, condensed/evaporated milk, plain condensed/evaporatedmilk, flavored, functional and other condensed milk, flavored milkdrinks, dairy only flavored milk drinks, flavored milk drinks with fruitjuice, soy milk, sour milk drinks, fermented dairy drinks, coffeewhiteners, powder milk, flavored powder milk drinks, fruit juices,vegetable juices, cream, cheese, processed cheese, spreadable processedcheese, unspreadable processed cheese, unprocessed cheese, spreadableunprocessed cheese, hard cheese, packaged hard cheese, unpackaged hardcheese, yoghurt, plain/natural yoghurt, flavored yoghurt, fruitedyoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt,probiotic drinking yoghurt, chilled and shelf-stable desserts,dairy-based desserts, soy-based desserts, chilled snacks, fromage fraisand quark, plain fromage frais and quark, flavored fromage frais andquark, savory fromage frais and quark, sweet and savory snacks, fruitsnacks, chips/crisps, extruded cereals and snacks, tortilla/corn chips,popcorn, pretzels, nuts, other sweet and savory snacks, snack bars,granola bars, breakfast bars, energy bars, fruit bars, other snack bars,meal replacement products, slimming products, convalescence drinks,ready meals, canned ready meals, frozen ready meals, dried ready meals,chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup,canned soup, dehydrated soup, instant soup, chilled soup, hot soup,frozen soup, pasta, canned pasta, dried pasta, chilled/fresh pasta,noodles, plain noodles, instant noodles, cups/bowl instant noodles,pouch instant noodles, chilled noodles, snack noodles, canned food,canned meat and meat products, canned fish/seafood, canned vegetables,canned tomatoes, canned beans, canned fruit, canned ready meals, cannedsoup, canned pasta, other canned-foods, frozen food, frozen processedred meat, frozen processed poultry, frozen processed fish/seafood,frozen processed vegetables, frozen meat substitutes, frozen potatoes,oven baked potato chips, other oven baked potato products, non-ovenfrozen potatoes, frozen bakery products, frozen desserts, frozen readymeals, frozen pizza, frozen soup, frozen noodles, other frozen food,dried food, dessert mixes, dried ready meals, dehydrated soup, instantsoup, dried pasta, plain noodles, instant noodles, cups/bowl instantnoodles, pouch instant noodles, chilled food, chilled processed meats,chilled fish/seafood products, chilled processed fish, chilled coatedfish, chilled smoked fish, chilled lunch kit, chilled ready meals,chilled pizza, chilled soup, chilled/fresh pasta, chilled noodles, oilsand fats, olive oil, vegetable and seed oil, cooking fats, butter,margarine, spreadable oils and fats, functional spreadable oils andfats, sauces, dressings and condiments, tomato pastes and purees,bouillon/stock cubes, stock cubes, gravy granules, liquid stocks andfonds, herbs and spices, fermented sauces, soy based sauces, pastasauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise,regular mayonnaise, mustard, salad dressings, regular salad dressings,low fat salad dressings, vinaigrettes, dips, pickled products, othersauces, dressings and condiments, baby food, milk formula, standard milkformula, follow-on milk formula, toddler milk formula, hypoallergenicmilk formula, prepared baby food, dried baby food, other baby food,spreads, jams and preserves, honey, chocolate spreads, nut-basedspreads, yeast-based spreads, toppings, syrups, and edible compositionscontaining whey protein, soy protein, and other plant and vegetablebased proteins.

In one embodiment, foods include alcoholic beverages, baby food, babyformula, baked goods, breakfast cereals, cheese, chewing gum, coffeewhiteners, condiments and relishes, confectionary and frostings,crackers, dairy products, egg products, fats and oils, fish products,frozen dairy, frozen dinners, fruit ices, gelatins and puddings, grainmixtures, granulated sugar, gravies, hard candy, imitation dairyproducts, coffee, coffee products and coffee beverages, jams andjellies, meat products, milk products, non-alcoholic beverages, nutproducts, grains and grain products, poultry, processed fruits,processed vegetables, reconstituted vegetables, ready to eat meals,salad dressings, seasonings and flavors, snack foods, soft candy, soups,sugar substitutes, sweet sauce, sweetener blends, table top sweeteners,tea, tea products, and tea beverages.

In a particular embodiment, foods include table top sweeteners andbeverages. Beverages include, but are not limited to, fruit juices, softdrinks, tea, coffee, beverage mixes, milk drinks, alcoholic and nonalcoholic beverages.

According to the present invention, “non-edible products” includesupplements, nutraceuticals, functional food products (e.g., any freshor processed food claimed to have a health-promoting and/ordisease-preventing properties beyond the basic nutritional function ofsupplying nutrients), pharmaceutical and over the counter products, oralcare products such as dentifrices and mouthwashes, cosmetic productssuch as sweetened lip balms and other personal care products that usesucralose and or other sweeteners.

The term “edible ingredient” herein means any edible component ormixture of components of food or food products, for example the edibleingredients which would typically be found in a recipe for human oranimal foods. Edible ingredients include natural and synthetic foodcomponents.

In general, over the counter (OTC) product and oral care productgenerally refer to product for household and/or personal use which maybe sold without a prescription and/or without a visit to a medicalprofessional. Examples of the OTC products include, but are not limitedto Vitamins and dietary supplements; Topical analgesics and/oranesthetic; Cough, cold and allergy remedies; Antihistamines and/orallergy remedies; and combinations thereof. Vitamins and dietarysupplements include, but are not limited to vitamins, dietarysupplements, tonics/bottled nutritive drinks, child-specific vitamins,dietary supplements, any other products of or relating to or providingnutrition, and combinations thereof. Topical analgesics and/oranesthetic include any topical creams/ointments/gels used to alleviatesuperficial or deep-seated aches and pains, e.g. muscle pain; teethinggel; patches with analgesic ingredient; and combinations thereof. Cough,cold and allergy remedies include, but are not limited to decongestants,cough remedies, pharyngeal preparations, medicated confectionery,antihistamines and child-specific cough, cold and allergy remedies; andcombination products. Antihistamines and/or allergy remedies include,but are not limited to any systemic treatments for hay fever, nasalallergies, insect bites and stings. Examples of oral care productinclude, but are not limited to mouth cleaning strips, toothpaste,toothbrushes, mouthwashes/dental rinses, denture care, mouth freshenersat-home teeth whiteners and dental floss.

In another embodiment, foods include ice creams, breakfast cereals,sweet beverages or solid or liquid concentrate compositions forpreparing beverages.

In various embodiments, edible compositions according to the presentinvention, comprising at least one edible ingredient, sucralose, and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof; wherein the edible ingredient includesbaked goods and baking mixes, beverages, alcoholic beverages andbeverage mixes, breakfast cereals, cheeses, chewing gum, coffee and tea,condiments and relishes, confections and frostings, dairy productsubstitutes, fats and oils, frozen dairy desserts and mixes, fruit andwater ices, gelatins, puddings, and fillings, gravies and sauces, petfoods, hard candy and cough drops, herbs, seeds, spices, seasonings,blends, extracts, and flavorings, jams and jellies, meat products, milkproducts, processed fruits and fruit juices, processed vegetables andvegetable juices, snack foods, soft candy, soups and soup mixes, sugarsubstitutes, sweet sauces, toppings, and syrups, whey protein, soyprotein, plant and vegetable based proteins, nutritional products &dietary supplements, pharmaceuticals, etc.

In other embodiments, edible compositions according to the presentinvention, comprising at least one edible ingredient, sucralose, and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1h)-one or salts,solvates, and/or esters thereof; wherein the edible ingredient includesalcoholic beverages, baby food, baby formula, baked goods, breakfastcereals, cheese, chewing gum, coffee whiteners, condiments & relishes,confectionery & frostings, crackers, dairy products, egg products, fats& oils, fish products, frozen dairy, frozen dinners, fruit ices,gelatins & puddings, grain mixtures, granulated sugar, gravies, hardcandy, imitation dairy products, coffee, coffee products and coffeebeverages, jams & jellies, meat products, milk products, non-alcoholicbeverages, nut products, grains and grain products, poultry, processedfruits, processed vegetables, reconstituted vegetables, ready to eatmeals, salad dressings, seasonings & flavors, snack foods, soft candy,soups, sugar substitutes, sweet sauce, sweetener blends, table topsweeteners, tea, tea products, and tea beverages.

The term “particles” herein means particles that have been formed from asolution or suspension by a spray drying process. The particlesaccording to the present invention may be of any size. In oneembodiment, the particles have a diameter of from about 20 μm to about200 μm, e.g., from about 50 μm to about 175 μm, or from about 75 μm toabout 150 μm. In another embodiment the spray dried particles can havesubstantially rounded shape, wherein about 40% to about 80% of the spraydried particles have a diameter of from about 20 μm to about 200 μm.Generally, the particles are within a more tightly controlled specificrange whose limits depend upon the particular application for which thecomposition is intended.

Compositions of the present invention comprise a plurality of particles.The particles of the present invention can have any suitable particlesize distribution, for example relatively large particles with a smallproportion of small particles. The particle size distribution can beunimodal or multimodal (e.g., the combination of two or more differentunimodal particle size distributions.

The particles of the present invention can be essentially spherical, orcan have a non-spherical shape defined by a length to diameter (L/D)ratio which is greater than 1. In one embodiment, the particlesgenerally have an L/D ratio in the range 5-10. In other embodiments, theL/D ratio can be about 1. Another useful characteristic is d₅₀, thespray droplet diameter that corresponds to the diameter of the dropletsthat make up 50% of the total liquid volume containing particles ofequal or smaller diameter. In one embodiment, the droplets will have ad₅₀ between 100 and 1000 μm in size, as determined by a drop-sizeanalyzer. In another embodiment of the invention, the particles have ad₅₀ between 400 and 800 μm in size, and are especially useful indissolution applications. For producing substantially homogenousparticles, the inventors have found that d₅₀ should be between 100 and200 μM in size with an L/D ratio of less than 2.0.

The particles of the present invention, as indicated herein, can beprepared e.g., by spray drying a solution or suspension of sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine -2(1H)-one or salts,solvates, and/or esters thereof. The spray dried solution or suspensioncan contain only solvent, sucralose, and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, or additionally contain a carrier suchas maltodextrin, starches, gum Arabic, or other acceptable carriers orfillers known in the art.

In one embodiment of the present invention, spray dried particles, eachcomprising 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, orsalts, solvates, and/or esters thereof and sucralose, have improveddissolution characteristics, or provide improved dissolutioncharacteristics to the compositions comprising the particles of thepresent invention, compared to non-spray dried particles (e.g., preparedby mixing or granulation). For example, such improved dissolutionproperties include an increased dissolution rate.

The particles of the present invention may be in various densitiesdepending on the intended use. In one embodiment of the presentinvention, the bulk density of the particles is between 0.25 and 0.75g/mL. In another embodiment the bulk density of the particles is between0.25 and 0.5 g/mL. In still another embodiment of the present invention,the particles have a moisture content between 0.25 and 0.5 wt %. In yetanother embodiment, the particles have a moisture content between 0.4and 0.5 wt %.

The particles of the present invention, comprising sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, can contain the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters at a concentration of about 50 wt. % to about 85wt. %, including about 55 wt. %, about 60 wt. %, about 65 wt. %, about70 wt. %, about 75 wt. %, or about 80 wt. %, inclusive of all ranges andsubranges therebetween.

4-Amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof used is useful for modulating (inducing,enhancing or inhibiting) the sweet taste or other taste properties ofthe sweeteners provided individually, or in combination with any foodproduct. Reduction in sweetener with increasing amounts of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof maintains or enhances the sweetnessprofile of a sweetener-containing composition or food withoutcompromising taste. Hence in one embodiment of the invention, the flavorof a sweetener, provided individually, or in combination with any foodproduct is enhanced in the presence of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof.

It is recognized that the concentration of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof needed to improve the flavor of a foodproduct will depend on many variables, including the specific type offood and its other ingredients, especially the presence of other knownsweet flavoring agents, the genetic variability and individualpreferences and health conditions of various human beings tasting thecompositions, and the subjective effect of the particular compound onthe taste of such chemosensory compounds. In one embodiment, the amountof 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine -2(1H)-one or salts,solvates, and/or esters thereof, by weight, ranges from about 0.001 ppmto about 100 ppm of the food product. In another embodiment, the amountranges from about 0.1 ppm to about 10 ppm of the food product.

The amount of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one orsalts, solvates, and/or esters thereof in the composition, or incombination with a food product, can be measured in relation to theamount of sweetener (e.g., sucralose) present in the composition or thefood product. In one embodiment, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sweetener weight ratio is from about1:50 (compound:sweetener) to about 1:10. In another embodiment, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sweetener weight ratio is from about1:30 to about 1:20.

In one embodiment of the present invention, spray dried particles, eachcomprising 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, orsalts, solvates, and/or esters thereof and sucralose, have an improvedsweetness delivery profile. In another embodiment of the presentinvention, the improvement comprises reducing the onset period of thesweetness delivery profile of a sweetener. In another embodiment, theimprovement comprises reducing the lingering period of the sweetnessdelivery profile of a sweetener. In yet another embodiment, theimprovement comprises reducing both the onset period and the lingeringperiod of the sweetness delivery profile of a sweetener.

In another embodiment of the present invention,4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one, or salts,solvates, and/or esters thereof induce shortening of sweetness onset andlingering periods of sucralose.

The ingestible composition whose sweetness delivery profile is improvedcan contain any sweetening amount of sucralose relative to4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof. In one embodiment, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sucralose weight ratio is from about1:2 to about 1:50. In another embodiment, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sucralose weight ratio is from about1:5 to about 1:40. In yet another embodiment, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sucralose weight ratio is from about1:8 to about 1:20.

For baked goods (e.g., cookies), the weight ratio of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof: sucralose is about 1:10 to about 1:20,about 1:12, about 1:14, about 1:16, or about 1:18. For table topsweeteners, the weight ratio ranges from about 1:15 to about 1:30, about1:17, about 1:19, about 1:20, about 1:22, about 1:24, about 1:26, orabout 1:28. For beverages, the weight ratio ranges from about 1:5 toabout 1:40; e.g., for hot cocoa the weight ratio ranges from about 1:20to about 1:30, about 1:23, about 1:25, or about 1:27; for colas theweight ratio ranges from about 1:5 to about 1:10, about 1:7 or about1:9. For frozen dairy products (e.g., ice cream) the weight ratio rangesfrom about 1:10 to about 1:20, about 1:13, about 1:16, or about 1:19.For yoghurt, the weight ratio ranges from about 1:8 to about 1:20, about1:10, about 1:12, about 1:14, about 1:16, or about 1:18.

In another embodiment of the present invention, the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one is present as itshydrochloride salt. In another embodiment, composition comprises4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride,sucralose and a carrier such as dextrose, lactose, maltodextrin orwater.

One embodiment of the present invention provides a process of making acomposition comprising solid particles of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, and sucralose by a spray dryingprocess. The term “spray-drying” broadly refers to processes involvingbreaking up liquid mixtures into small droplets (atomization) andrapidly removing solvent from the mixture in a spray-drying apparatuswhere there is a strong driving force for evaporation of solvent fromthe droplets. For example,4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, and the sucralose are both dissolved ordispersed in a common solvent (e.g., water), and the resulting solutionand or dispersion is spray dried. The resulting spray dried particleseach comprise an intimate and essentially homogeneous blend of the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof and the sucralose. Solid particles ofthe claimed composition prepared by spray drying have differentdissolution and stability properties compared to essentially the samecomposition prepared by other methods Solvents suitable for spray-dryingcan be any liquid in which each of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof and the sucralose are soluble and/ordispersed. Preferably, the solvent is also volatile with a boiling pointof 150° C. or less. In addition, the solvent should have relatively lowtoxicity. In some embodiments, suitable spray drying solvents includewater, alcohols such as methanol, ethanol, n-propanol, iso-propanol, andbutanol; ketones such as acetone, methyl ethyl ketone and methyliso-butyl ketone; esters such as ethyl acetate and propylacetate; andvarious other solvents such as acetonitrile, methylene chloride,toluene, and 1,1,1-trichloroethane. Lower volatility solvents such asdimethyl acetamide or dimethylsulfoxide can also be used. Mixtures ofsolvents, such as 50% methanol and 50% acetone, can also be used, as canmixtures with water, so long as the sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof are sufficiently soluble to make thespray-drying process practicable.

The strong driving force for solvent evaporation is generally providedby maintaining the partial pressure of solvent in the spray-dryingapparatus well below the vapor pressure of the solvent at thetemperature of the drying droplets. This is accomplished by (1)maintaining the pressure in the spray-drying apparatus at a partialvacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets witha warm drying gas; or (3) both (1) and (2). In addition, a portion ofthe heat required for evaporation of solvent may be provided by heatingthe spray solution.

The relative proportion of each components namely,4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof and at least one sweetener in the solidparticle will depend on the ratio and solubilities of the two componentsin the solvent utilized for spray drying. In one embodiment the relativeproportion ranges from about 0.002% to about 50% weight of thesweetener, and about 99.008% to about 50% weight of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof. In another embodiment the relativeproportion ranges from about 20% to about 50% weight of the sweetener,and about 80% to about 50% weight of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof.

In one embodiment, a sweet taste modulating amount of the composition ofthe present invention is incorporated into food products or formulationsoptionally in the presence of known sweeteners. e.g., so that the sweetflavor modified food product has an increased sweet taste as compared tothe food product without the sweet taste modulating amount of thecomposition, as judged by human beings or animals in general, or in thecase of formulations testing, as judged by a majority of a panel of atleast 3 human taste testers, via procedures commonly known in the field.In another embodiment, the compositions of the present invention can beformulated in flavor preparations to be added to food or products.

In other embodiments, the compositions of the present invention allowthe amount of sucralose, e.g., in an ingestible compositions such as afood, to be reduced due the sweetness enhancing effects of the4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof. The amount of reduction of thesucralose, relative to the amount of sucralose in the conventionalsucralose-containing ingestible composition without4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts,solvates, and/or esters thereof, can be in the range of about 10 wt. %to about 90 wt. %, including reductions of about 15 wt. %, about 20 wt.%, about 25 wt. %, 30 about wt. %, about 35 wt. %, about 40 wt. %, about45 wt. %, about 50 wt. %, about 55 wt. %, about 60 wt. %, about 65 wt.%, about 70 wt. %, about 75 wt. %, about 80 wt. %, or about 85 wt. %,inclusive of all ranges and subranges therebetween.

The amount of 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one orsalts, solvates, and/or esters thereof present in ingestiblecompositions having reduced levels of sucralose (as disclosed herein)can range from about 0.1 ppm to about 2000 ppm, including about 0.5 ppm,about 1 ppm, about 2 ppm, about 3 ppm, about 4 ppm, about 5 ppm, about 6ppm, about 7 ppm, about 8 ppm, about 9 ppm, about 10 μm, about 15 ppm,about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm,about 50 ppm, about 60 ppm, about 70 ppm, about 80 ppm, about 90 ppm,about 100 ppm, about 150 ppm, about 200 ppm, about 250 ppm, about 300ppm, about 350 ppm, about 400 ppm, about 500 ppm, about 600 ppm, about700 ppm, about 800 ppm, about 900 ppm, about 1000 ppm, about 1200 ppm,about 1400 ppm, about 1600 ppm, about 1800 ppm, inclusive of all values,ranges and subranges therebetween.

Similarly, the compositions of the present invention can improve thesweetness delivery profile of sucralose-containing ingestiblecompositions.

When the sweetness or sweetness delivery profile characteristics ofcompositions containing sucralose are compared with compositionscomprising combinations of sucralose and4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one or salts, solvatesand/or esters thereof, any conventional organoleptic techniques may beused as described herein, including paired comparison tests, differencetesting, time intensity testing, descriptive analysis, etc. Whencompositions are deemed to have “substantially” the same sweetness orsweetness delivery profile, these characteristics are not readilydistinguishable using conventional organoleptic techniques.

In another embodiment food products that comprise the compositions ofthe present invention are prepared by means of conventional mixing,dissolving, granulating the ingredients into various forms comprisingsolid, semi-solid, and liquid foods. Various additives may be mixed,ground, or granulated with the compositions of this invention to formsuitable food materials. Compositions of the invention may be formulatedinto foods so that they are delivered as a dry powder or a liquidsuspension. In one embodiment, the composition of the present inventionis formulated as a liquid or as a paste at the time of preparation. Inother embodiments the composition is formulated as a dry powder with aliquid, typically water, added at a later time but prior to mixing withthe other food ingredients.

Thieno[2,3-d]pyrimidine derivatives including4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one can be prepared bysynthetic methods known to one skilled in the art. In one embodiment, asillustrated in Scheme 1 below, thieno[2,3-d]pyrimidine derivatives areprepared from 2-aminothiophene derivatives via the Gewald reaction (Chenet al., Synthetic Communication 2004, 34, 3801 and references citedtherein; Elmegeed et al., Eur. J. Med. Chem. 2005, 40, 1283 andreferences cited therein). Additional details can be found in theInternational Application No. PCT/US2008/065650, filed Jun. 3, 2008 andentitled “Modulation of Chemosensory Receptors and Ligands AssociatedTherewith”, the content of which is herein incorporated by reference intheir entirety for all purposes. Thus, 2-aminothiophene derivatives arekey intermediates for preparing thieno[2,3-d]pyrimidine derivativesincluding 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one.

In one embodiment, the present invention provides a process of preparinga 2-aminothiophene derivative having structural Formula (a):

The process comprises mixing a compound having structural Formula (b):

with a compound having structural Formula (c)

in the presence of an organic amine at a temperature of about 0° C. orbelow to obtain a reaction mixture; maintaining the reaction mixture ata temperature of about 0° C. or below for about 30 to about 90 minutes;concentrating the reaction mixture to obtain a slurry; and filtering theslurry to obtain the compound having structural Formula (a) as solidparticles; wherein: R¹ is hydrogen, alkyl, heteroalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl; R² is hydrogen, alkyl,heteroalkyl, alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;or alternatively, R¹ and R², together with the atoms to which they areattached, form a carbocyclic ring or heterocyclic ring; X is CN or—C(O)R³; R³ is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR⁴,or N(R⁴)₂; and each R⁴ is independently hydrogen, alkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl. In one embodiment of thepresent process, R¹ is hydrogen or alkyl; R² is hydrogen or alkyl; and Xis CN. In another embodiment of the present process, R¹ is methyl; R² ismethyl; and X is CN.

In one embodiment, the mixing step comprises mixing a solution of thecompound having structural Formula (b) with a solution of the compoundhaving structural Formula (c) in the presence of an organic amine. Eachof the solutions can have the same or different solvent. In oneembodiment, each of the solutions can have the same or different alcoholsolvent. In one embodiment of the present process, the mixing stepcomprises adding an alcohol solution of the compound having structuralFormula (b) to an alcohol solution of the compound having structuralFormula (c) and the organic amine at a temperature of about 0° C. orbelow. The temperature is maintained at about 0° C. or below throughoutthe adding step. Thus, the adding process needs to be controlled at sucha rate that the temperature of the resulting reaction mixture dose notarise to above 0° C. Depending on the amount of material and the meansof controlling temperature, the duration of the adding step variessubstantially. The an alcohol solution of the compound having structuralFormula (c) and the organic amine can be prepared by mixing the compoundhaving structural Formula (c) and the organic amine in an alcoholsolvent at a temperature of about 10° C. or below with the temperatureof about 5° C. or below more preferred. The alcohol can be methanol,ethanol, n-propanol, isopropanol, or a combination thereof.

In one embodiment, the reaction mixture is maintained at a temperatureof about 0° C. or below for about 45 to about 75 minutes. In anotherembodiment, the reaction mixture is maintained at a temperature of about0° C. or below for about 60 minutes. In one embodiment, the temperaturefor the mixing step is from about −20° C. to about 0° C. In anotherembodiment, the temperature for the mixing step is from about −15° C. toabout 0° C. In another embodiment, the temperature for the mixing stepis from about −10° C. to about −5° C. In one embodiment, the temperaturefor the maintaining step is from about −20° C. to about 0° C. In anotherembodiment, the temperature for the maintaining step is from about −15°C. to about 0° C. In another embodiment, the temperature for themaintaining step is from about −10° C. to about −5° C.

In one embodiment of the present process, the reaction mixture isconcentrated by evaporating the solvent. The evaporation can beaccomplished by any means known to one skilled in the art including, butare not limited to applying vacuum to the reaction mixture, elevatingtemperature of the reaction mixture, spinning the reaction mixture on asolid surface, stirring the reaction mixture, blowing air or other gasto the surface of the reaction mixture, and any combination thereof.Preferably, the temperature of the reaction mixture during theevaporation process is not higher than about 50° C. In one embodiment,the evaporation is accomplished by rotovaping the reaction mixture at atemperature of about 50° C. or below with the temperature of about 40°C. or below more preferred.

In one embodiment, the concentration step comprises reducing the volumeof the reaction mixture to about 60% or less of its original volume. Inanother embodiment, the concentration step comprises reducing the volumeof the reaction mixture to about 50% or less of its original volume. Inanother embodiment, the concentration step comprises reducing the volumeof the reaction mixture to about 40% or less of its original volume. Inanother embodiment, the concentration step comprises reducing the volumeof the reaction mixture to about 30% or less of its original volume. Inyet another embodiment, the concentration step comprises evaporating allor most of the solvent to obtain a dried or semi-dried reaction mixtureand re-adding the solvent to the dried or semi-dried reaction mixture toobtain a slurry. The amount of the re-added solvent can be from about30% to about 60% of the original amount.

In one embodiment, the filtrate of the filtering step, i.e., the solventpassing through the filter, can be concentrated to obtain a slurryaccording to the procedure described above. The slurry can be filteredto obtain the compound having structural Formula (a) as solid particles.

In one embodiment of the present process, the molar ratio of thecompound having structural formula (b) to the compound having structuralformula (c) is from about 1:0.9 to about 1:1.1. In another embodiment ofthe present process, the molar ratio of the compound having structuralformula (b) to the compound having structural formula (c) is about 1:1.In one embodiment of the present process, the molar ratio of thecompound having structural formula (c) to the organic amine is fromabout 5.1:1 to about 4.9:1. In another embodiment of the presentprocess, the molar ratio of the compound having structural formula (c)to the organic amine is about 5:1.

In one embodiment, the process described above further comprises washingthe solid particles of the compound having structural Formula (a) withan eluting solvent, wherein the eluting solvent is a mixture of analcohol solvent and an alkane hydrocarbon solvent. In one embodiment,the volume ratio of the alcohol solvent to the alkane hydrocarbonsolvent is from about 1:9 to about 1:2. In another embodiment, thevolume ratio of the alcohol solvent to the alkane hydrocarbon solvent isfrom about 1:7 to about 1:3. In another embodiment, the volume ratio ofthe alcohol solvent to the alkane hydrocarbon solvent is about 1:4.

The above-described process provides a manufacturable process for thepreparation of 2-aminothiophene derivatives including2-amino-3-cyano-4,5-dimethylthiophene. By “manufacturable process”, itis meant a large scale process suitable for industrial production.Specifically, the present process involves short reaction times therebyminimizing time spent in the plant and reducing plant costs. The processalso provides a highly pure solid material that is easy to handle. Forexample, as described hereinbelow in Example 13, the 2-aminothiopheneproduct can be obtained after a simple wash protocol with greater than99% purity by HPLC. That is, the present invention provides a process ofpreparing 2-aminothiophene that does not comprise chromatographicpurification . The reaction yield is mostly from about 60 to about 70%.Furthermore, the reaction can be run at higher concentrations therebyreducing solvent costs and being more environmentally friendly.

The term “alkyl” herein means a saturated branched, straight-chain orcyclic organic radical derived by the removal of one hydrogen atom froma single carbon atom of a parent alkane. The term “alkyl” includescycloalkyl. In one embodiment of the present invention, the alkyl groupcontains from 1 to 12 carbon atoms (C₁-C₁₂ alkyl). In another embodimentof the present invention, the alkyl group contains from 1 to 6 carbonatoms (C₁-C₆ alkyl). Examples of alkyl groups include, but are notlimited to, methyl; ethyl; propyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (1-butyl), cyclobutan-1-yl, etc.; cyclopropyl,cyclobutyl, cyclopentyl, and the like. The alkyl group may be furtheroptionally substituted.

The term “alkenyl” herein means an unsaturated branched, straight-chainor cyclic organic radical having at least one carbon-carbon double bondderived by the removal of one hydrogen atom from a single carbon atom ofa parent alkene. The term “alkenyl” includes cycloalkenyl. The group maybe in either the cis or trans conformation about the double bond(s). Inone embodiment of the present invention, the alkenyl group contains from2 to 14 carbon atoms (C₂-C₁₄ alkyl). In another embodiment of thepresent invention, the alkenyl group contains from 2 to 8 carbon atoms(C₂-C₈ alkyl). Typical alkenyl groups include, but are not limited to,ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. Thealkenyl group may be further optionally substituted.

The term “aryl” herein means a monovalent aromatic hydrocarbon groupderived by the removal of one hydrogen atom from a single carbon atom ofa parent aromatic ring system, as defined herein. Examples of aryl groupinclude, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexylene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthaleneand the like. In some embodiments, an aryl group comprises from 6 to 20carbon atoms (C₆-C₂₀ aryl). In other embodiments, an aryl groupcomprises from 6 to 15 carbon atoms (C₆-C₁₅ aryl). In still otherembodiments, an aryl group comprises from 6 to 15 carbon atoms (C₆-C₁₀aryl). The aryl group may be further optionally substituted.

The term “heteroaryl” herein means a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring systems, as defined herein. Examples ofheteroaryl group include, but are not limited to, groups derived fromacridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine. The heteroaryl group may be further optionally substituted.

The term “heteroalkyl” herein means an alkyl group, respectively, inwhich one or more of the carbon atoms (and optionally any associatedhydrogen atoms), are each, independently of one another, replaced withthe same or different heteroatoms or heteroatomic groups. Typicalheteroatoms or heteroatomic groups which can replace the carbon atomsinclude, but are not limited to, —O—, —S—, —N—, —Si—, —NH—, —S(O)—,—S(O)₂—, —S(O)NH—, —S(O)₂NH— and the like and combinations thereof. Theheteroatoms or heteroatomic groups may be placed at any interiorposition of the alkyl group. The heteroalkyl group may be furtheroptionally substituted.

The term “arylalkyl” herein means an alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group as, as defined herein.Typical arylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. In some embodiments, anarylalkyl group is (C₆-C₃₀) arylalkyl, e.g., the alkyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkyl moiety of the arylalkyl group is (C₁-C₈) alkyl and the arylmoiety is (C₆-C₁₂) aryl. In still other embodiments, an arylalkyl groupis (C₆-C₁₅) arylalkyl, e.g., the alkyl moiety of the arylalkyl group is(C₁-C₅) alkyl and the aryl moiety is (C₆-C₁₀) aryl. The arylalkyl groupmay be further optionally substituted.

The term “heteroarylalkyl” herein means an alkyl group in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heteroaryl group. In some embodiments,the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., thealkyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and the heteroarylmoiety is a 5-15-membered heteroaryl. In other embodiments, theheteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkylmoiety is (C₁-C₃) alkyl and the heteroaryl moiety is a 5-10 memberedheteroaryl. The heteroarylalkyl group may be further optionallysubstituted.

The term “carbocyclic” herein means a saturated or unsaturated cyclicalkyl or alkenyl radical. Examples of carbocyclic group include, but arenot limited to, groups derived from cyclopropane, cyclobutane,cyclopentane, cyclohexane, and the like. In some embodiments, acarbocyclic group comprises from 3 to 10 ring atoms (C₃-C₁₀ cycloalkyl).In other embodiments, a carbocyclic group comprises from 3 to 7 ringatoms (C₃-C₇ cycloalkyl). The carbocyclic group may be furtheroptionally substituted.

The term “heterocyclic” herein means a saturated or unsaturated cyclicalkyl or alkenyl radical in which one or more carbon atoms (andoptionally any associated hydrogen atoms) are independently replacedwith the same or different heteroatom. Typical heteroatoms to replacethe carbon atom(s) include, but are not limited to, B, N, P, O, S, Si,etc. Examples of heterocyclic group include, but are not limited to,groups derived from epoxides, azirines, thiiranes, imidazolidine,morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone,quinuclidine, borolane, dioxaborolane, and the like. In someembodiments, the heterocyclic group comprises from 3 to 10 ring atoms(3-10 membered heterocyclic). In other embodiments, the heterocyclicgroup comprise from 5 to 7 ring atoms (5-7 membered heterocyclic). Aheterocyclic group may be substituted at a heteroatom, for example, anitrogen atom, with a (C₁-C₆) alkyl group. As specific examples,N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl,N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinylare included within the definition of “heterocyclic.” A heterocyclicgroup may be attached to the remainder of the molecule via a ring carbonatom or a ring heteroatom. The heterocyclic group may be furtheroptionally substituted.

The term “alcohol” herein means an organic compound in which a hydroxylgroup (—OH) is bound to a carbon atom of an alkyl or substituted alkylgroup. The alcohol includes primary, secondary, and tertiary alcohols.Examples of alcohol include, but are not limited to, methanol, ethanol,n-propanol, isopropanol, n-butanol, s-butanol, and t-butanol. Thealcohol may be further optionally substituted.

The term “alkane hydrocarbon” herein means an organic compound or amixture of organic compounds which consist of hydrogen and carbon andcontain no or trace amount of unsaturated carbon-carbon bond. Examplesof alkane hydrocarbon include, but are not limited to, hexanes andheptanes.

The term “organic amine” herein denotes a compound having structuralformula N(R)₃, wherein each R is independently hydrogen, alkyl, alkenyl,aryl, heteroaryl, heteroalkyl, arylalkyl, or heteroarylalkyl, oralternatively, two of R, together with the nitrogen atom to which theyare attached, form a heterocyclic ring. Examples of organic amineinclude, but are not limited to, methylamine, dimethylamine,diethylamine, methylethylamine, triethylamine, diisopropylethylamine(DIEA), morpholine, piperidine, and combinations thereof.

The term “substituted”, when used to modify a specified group orradical, means that one or more hydrogen atoms of the specified group orradical are each, independently of one another, replaced with the sameor different substituent(s). Substituent groups useful for substitutingsaturated carbon atoms in the specified group or radical include, butare not limited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S, ═S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻), —P(O)(OR^(b))(O⁻),P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, arylalkyl, alkyldiyl,substituted alkyldiyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroalkyl, substituted heteroalkyl, heteroalkyldiyl,substituted heteroalkyldiyl, heteroaryl, substituted heteroaryl,heteroarylalkyl substituted heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c) are taken together with the nitrogen atomto which they are bonded form a cycloheteroalkyl ring which mayoptionally include from 1 to 4 of the same or different additionalheteroatoms selected from the group consisting of O, N and S. Asspecific examples, —NR^(c)R^(c) is meant to include —NH₂, —NH-alkyl,N-pyrrolidinyl and N-morpholinyl.

EXAMPLES

The term “Compound A” as used hereinblow refers to“4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one” or“4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride”.

Example 1

General Procedure for Preparation of Spray Dried Solid Particles

Solid particles were prepared using a spray-drying apparatus.4-Amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride, andsucralose were mixed in a solvent (water) together with maltodextrin toform a spray solution. A Buchi lab spray dryer model # B-290 wasutilized for the lab formulation and procedure work for spray drying.Solid particles comprising the composition of the invention wereprepared according to the spray dried formulation in Table I.

The solid particles were prepared according to the following procedure:

Water was pre-weighed in a beaker and each of Star-Dri 10 Maltodextrin,Sucralose and 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride (100× in PG) were pre-weighted and set aside separately.The water beaker was placed on a heat plate equipped with a stirring barand the stir knob (700-800 rpm) turned on to create a vortex in thewater beaker. The maltodextrin was added with stirring until all themaltodextrin dissolved. Sucralose and COMPOUND A (3% in PG) were addedand the stirring continued until all ingredients dissolved. The solutionwas then spray dried using a Buchi mini spray dryer with specificationsof inlet temperature=155-160° C., outlet temperature=100° C. and Pump%=30. The brix of the solution is 42.1

TABLE I Actual weight Percent of Dry Ingredient Percentage (grams)(wt/wt) Star-Dri 10 Maltodextrin 38.30400 38.3040 95.76000 Sucralose1.60000  1.60000 4.00000 4-amino-5,6-dimethylthieno 3.20000  3.20000.24000 [2,3-d]pyrimidine-2(1H)- one hydrochloride (3% in propyleneglycol) Water 56.89600 56089600 0.00000 Total 100.00000 100.00000100.0000

Example 2

For comparison purposes, dry blends of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine -2(1H)-one hydrochloride andsucralose were made to demonstrate that solid particles with uniformratios of dimethylthieno[2,3-d]pyrimidine-2(1H)-thionehydrochloride:sweetener were not obtained, as determined by HPLC.

Example 3

For comparison of dissolution rates, sucralose (Splenda®), dry blends of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride andsucralose, and spray dried particles comprising4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one and sucralose weredissolved in beverage or liquid, and the time taken for each compositionto go into solution was measured visually. Table II gives thedissolution rates. The net weight of each of the sucralose, the dryblended 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride and sucralose, and spray dried particles comprising4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one and sucralose, andspray dried 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride and sucralose, and spray dried particles comprising4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one and sucralose induplicate runs was 1.00 g. The volume of tested beverage or liquid was120 mL. 1.00 g of each composition was dissolved into 120 mL of testliquid, using a 1″ stir bar over a magnetic stirrer (model # FisherScientific Isotemp) at 600-700 rpms

TABLE II Water Cold Water Hot Water Ice Tea Hot Coffee Ingredients 20°5° 66° C. 5° C. 66° C. Splenda Packet 40 1 minute, 8 5 seconds 1 minute,52 15 seconds seconds seconds seconds dry blended 4- >5 >5 minutes 1minute, 50 >5 minutes 3 minutes, amino-5,6- minutes seconds 25 secondsdimethylthieno[2,3- d]pyrimidine- 2(1H)-one hydrochloride and sucralose,in duplicate Spray Dried 4- 35 1 minute, 2 5 seconds 1 minutes, 57 25seconds amino-5,6- seconds seconds seconds dimethylthieno[2,3-d]pyrimidine- 2(1H)-one hydrochloride and sucralose, in duplicate

Example 4

Hot Cocoa

Hot cocoa compositions were prepared using the following ingredients andevaluated for sweetness and/or lingering taste. Formulation (b)comprising reduced sucralose and 10 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one had approximatelythe same sweetness as formulation (a) which comprised 100% sucralose.

TABLE III Sample weight Sample weight (grams) (grams) 100% sucraloseReduced sucralose hot cocoa hot cocoa Ingredients (a) (b) Instant nonfat dry milk Fortified 6.00 6.00 with Vitamin A &D, Kroger QualityIngredients, Creamer 4.00 4.00 #4403 Alto cocoa, Guittard 4.00 4.00 KelCam 280, CP Kelco 0.060 0.060 Vanilla Flavor 0.10 0.100 Salt 0.200 0.200Sucralose 0.0350 0.0176 Maltodextrin 5.605 5.42244-amino-5,6-dimethylthieno[2,3- 0 0.2000 d]pyrimidine-2(1H)-one (10 ppmneat) 0.1% in Propylene Glycol Total Weight 20.000 20.000

The hot cocoa powder is reconstituted with 6 fl. oz. hot water (20 gpowder+approximately 180 g hot water);4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one will beapproximately 1 ppm as consumed.

Human Taste Test:

Paired comparison taste test with Hot Cocoa with 175 ppm Sucralose vs.Hot Cocoa with 87.5 ppm Sucralose. Panelists evaluate two hot cocoasamples in a paired comparison taste test procedure and are instructedto select the sweeter of the two samples. They perform a total of threepaired comparison tests each containing the following samples: Hot Cocoawith 175 ppm Sucralose vs. Hot Cocoa with 87.5 ppm Sucralose.

Conclusions:

-   -   Panelists found Hot Cocoa with 175 ppm Sucralose was        significantly sweeter than Hot Cocoa with 87.5 ppm Sucralose        (p<0.05). 42 of 45 tests indicated Hot Cocoa with 175 ppm        Sucralose was the sweeter sample.

TABLE IV Sample selected as sweeter by panelists Hot Cocoa with 175 ppmSucralose vs. Hot Cocoa with 87.5 ppm Sucralose. n = 45 (15 panelists ×3 reps). Samples Test 1 Test 2 Test 3 Total Hot Cocoa with 175 ppm 13 1415 42 Sucralose Hot Cocoa with 87.5 ppm 2 1 0 3 Sucralose Total 15 15 1545 Hot Cocoa with 175 ppm 0.004 <0.004 <0.004 <0.001 Sucralose selected(p-value)Human Taste Test:

Paired comparison taste test with Hot Cocoa with 175 ppm Sucralose vs.Hot Cocoa with 87.5 ppm Sucralose+10 ppm Compound A. Panelists evaluatetwo hot cocoa samples in a paired comparison taste test procedure andare instructed to select the sweeter of the two samples. They perform atotal of three paired comparison tests each containing the followingsamples: Hot Cocoa with 175 ppm Sucralose vs. Hot Cocoa with 87.5 ppmSucralose+10 ppm Compound A.

Conclusions:

Panelists found Hot Cocoa with 175 ppm Sucralose was not significantlydifferent than Hot Cocoa with 87.5 ppm Sucralose+10 ppm Compound A(p<0.10). 26 of 45 tests indicated Hot Cocoa with 87.5 ppm Sucralose+10ppm Compound A was the sweeter sample.

TABLE V Sample selected as sweeter by panelists Hot Cocoa with 175 ppmSucralose vs. Hot Cocoa with 87.5 ppm Sucralose + 10 ppm Compound A. n =45 (15 panelists × 3 reps). Samples Test 1 Test 2 Test 3 Total Hot Cocoawith 175 ppm 8 6 5 19 Sucralose Hot Cocoa with 87.5 ppm 7 9 10 26Sucralose Total 15 15 15 45 Hot Cocoa with 175 ppm >0.774 0.607 0.3020.371 Sucralose selected (p-value)

Example 5

Pudding

Pudding compositions were prepared using the following ingredients andevaluated for sweetness and/or lingering taste. Composition (e)comprising 50% sucralose and 8:5 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one had approximatelythe same sweetness as composition (c) which comprised 100% sucralose.Composition (d) comprising 50% sucralose and 7.5 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one was not as sweetas composition (c) which comprised 100% sucralose.

TABLE VI Sample weight Sample weight Sample weight (grams) (grams)(grams) 100% sucralose 50% sucralose 50% sucralose pudding puddingpudding Ingredients (c) (d) (e) Albertson's Lowfat milk 60.0 60.0 60.0Vitamin A & D, 1% Milk Fat National 465 Food Starch 5.0 5.0 5.0 ModifiedJerzee Blend TUF-1HD 1.5 1.5 1.5 175545, Diehl Salt 0.25 0.25 0.25 PureVanilla Extract, 0.5 0.5 0.5 Kroger Sucralose 0.0250 (250 ppm) 0.0125(125 ppm) 0.0125 (125 ppm) Color yellow #5 0.00150 0.00150 0.00150 Water32.7235 31.986 31.8860 4-amino-5,6- 0 0.75 0.85 dimethylthieno[2,3- (7.5ppm neat) (8.5 ppm neat) d]pyrimidine-2(1H)-one* 0.1% in PropyleneGlycol Total Weight 100.00 100.00 100.00*4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one will beapproximately 7.5-8.5 ppm as consumed (100 g cup of pudding).

30 panelists evaluated compositions (c) and (e) in a paired comparisontaste test. The panelists were asked to pick the sweeter of the twosamples. All the samples were completely randomized. Twenty-one of thethirty panelists rated composition (e) as sweeter than composition (c)as shown in Table V.

TABLE VII Results of the paired comparison test: 100% sucralose versus50% sucralose + 8.5 ppm 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one vanilla pudding, n = 30 (10 panelists × 3 rep.) All Tests AllTests All Tests Samples 1 vs 2 3 vs 4 5 vs 6 Totals 100% sucralose 5 2 29 vanilla pudding 50% sucralose + 5 8 8 21 8.5 ppm of Compound A vanillapudding Total 10 10 10 30

Example 6

Cookies

Cookies were prepared using the following ingredients and evaluated forsweetness and/or lingering taste. Composition (g) comprising 100 ppm ofsucralose and 22 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one had approximatelythe same sweetness as composition (f) which comprised 100% sucralose.(200 ppm of sucralose).

TABLE VIII Sample weight (grams) Sample weight (grams) 50% reducedsucralose 100% sucralose cookies cookies Ingredients (f) (g) Flour 205.3205.3 Baking soda 2.5 2.5 Butter, Salted 0.5 0.5 Butter 125.05 125.05Egg 20.02 20.02 Vanilla 2.5 2.5 Sucralose 0.09 (200 ppm) 0.045 (100 ppm)Sugar 74.84 74.84 Water 15 15 Compound A (1% in 0 0.983 PropyleneGlycol) (22 ppm neat) Total Weight 445.8 446.744-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one will beapproximately 15 ppm as consumed (30 gram cookie).Human Taste Test:

Paired comparison taste test with 100 ppm Sucralose Sugar Cookie+22 ppmCompound A vs. 200 ppm Sucralose Sugar Cookie.

Procedure:

Panelists evaluate two cookies in a paired comparison taste testprocedure and are instructed to select the sweeter of the two samples.They perform a total of three paired comparison tests each containingthe following samples: 100 ppm Sucralose Sugar Cookie+22 ppm Compound Avs. 200 ppm Sucralose Sugar Cookie.

Products:

Sugar Cookie=flour, baking soda, salt, butter, egg, vanilla, sugar,water, sucralose, and optionally Compound A

Conclusions:

Panelists found the 200 ppm Sucralose Sugar Cookie was not significantlydifferent in sweetness than the “100 ppm Sucralose Sugar Cookie+22 ppmCompound A” (p>0.10). 23 of 42 tests indicated 200 ppm Sucralose SugarCookie was the sweeter sample.

1/14 panelists chose the 200 ppm Sucralose Sugar Cookie as the sweetersample in all three paired comparisons. 8/14 panelists chose the 200 ppmSucrulose Sugar Cookie as the sweeter sample in two paired comparisontests. 4114 panelists chose the 200 ppm Sucralose Sugar Cookies as thesweeter sample in one paired comparison test. 1/14 panelists chose the200 ppm Sucralose as the sweeter sample in zero paired comparison tests.

TABLE IX Sample selected as sweeter by panelists: 200 ppm SucraloseSugar Cookie vs. 100 ppm Sucralose Sugar Cookie + 22 ppm Compound A. n =42 (14 panelists × 3 reps). Samples Test 1 Test 2 Test 3 Total 200 ppmSucralose Sugar Cookie 6 9 8 23 100 ppm Sucralose Sugar Cookie + 8 5 619 22 ppm Compound A Total 14 14 14 42 200 ppm Sucralose SugarCookie >0.791 0.424 0.791 0.644 selected (p-value)

Example 7

Cola-Soda

Cola-soda was prepared using the following ingredients and evaluated forsweetness and/or lingering taste. Composition (i) comprising 50%sucralose and 12 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride hadapproximately the same sweetness as composition (h) which comprised 100%sucralose.

TABLE X Sample weight Sample weight (grams) 100% (grams) 50% sucralosecola-soda sucralose cola-soda Ingredients (h) (i) Cola Emulsion 0.450.45 Phosphonic acid 50%, Astaris 0.40 0.40 Ace-K, Nutrinova 0.0025 0.00Caramel color #105, DD 0.150 0.150 Williamson Caramel color #050, DD0.05 0.05 Williamson Sucralose 0.02 0.01 Carbonated water 98.8075 98.82Propylene Glycol 0.12 0 4-amino-5,6- 0 ppm 0.12 dimethylthieno[2,3- (12ppm neat) d]pyrimidine-2(1H)-one hydrochloride (1% in propylene glycol)Total Weight 100.0000 100.0000Human Taste Tests:

Cola Paired Comparison of Cola+200 ppm Sucralose+25 ppm AcesulfamePotassium vs. Cola+100 ppm Sucralose

Procedure:

Panelists evaluated two sweet solutions in a paired comparison tastetest procedure and were instructed to select the sweeter of the twosamples. Panelists performed a total of three paired comparison testseach containing the following samples: Cola+200 ppm Sucralose+25 ppmAcesulfame Potassium vs. Cola+100 ppm Sucralose.

Products:

Cola+Sucralose=caramel color 105, caramel color 050, sucralose,acesulfame K, cola emulsion E, phosphoric acid, propylene glycol,carbonated water.

Conclusions:

Panelists found that the Cola+200 ppm Sucralose+25 ppm AcesulfamePotassium sample was significantly sweeter than Cola+100 ppm Sucralose(p<0.05). 31 of 34 tests indicated Cola+200 ppm Sucralose+25 ppmAcesulfame Potassium was the sweeter sample; panelists coulddiscriminate the sweetness difference between the two samples.

TABLE XI Sample selected as sweeter by panelists Cola + 200 ppmSucralose vs. Cola + 100 ppm Sucralose. n = 34 (17 panelists × 2 reps).Samples Test 1 Test 2 Total Cola + 200 ppm Sucralose + 25 ppm 14 17 31Acesulfame Potassium Cola + 100 ppm Sucralose 3 0 3 Total 17 17 34Cola + 200 ppm Sucralose selected (p-value) 0.006 <0.001 <0.001Cola Paired Comparison

Cola+200 ppm Sucralose+25 ppm Acesulfame Potassium vs. Cola+100 ppmSucralose+12 ppm 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride

Procedure:

Panelists evaluated two sweet solutions in a paired comparison tastetest procedure and were instructed to select the sweeter of the twosamples. They performed a total of three paired comparison tests eachcontaining the following samples: Cola+200 ppm Sucralose+25 ppmAcesulfame Potassium vs. Cola+100 ppm Sucralose+12 ppm4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride.

Products:

Cola+Sucralose=caramel color 105, caramel color 050, sucralose,acesulfame K, cola emulsion E, phosphoric acid, propylene glycol,carbonated water, 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride.

Conclusions:

Panelists found that Cola+200 ppm Sucralose+25 ppm Acesulfame Potassiumwas not significantly different in sweetness than Cola+100 ppmSucralose+12 ppm 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride (p>0.1). 18 of 34 tests indicated that Cola+200 ppmSucralose+12 ppm 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-onehydrochloride was the sweeter sample; panelists could not discriminatethe sweetness difference between the two samples. The removal ofAcesulfame Potassium also reduces or eliminates the bitter or off tastefrom the drink.

TABLE XII Sample selected as sweeter by panelists Cola + 200 ppmSucralose + 25 ppm Acesulfame Potassium vs. Cola + 100 ppm Sucralose +12 ppm 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine- 2(1H)-onehydrochloride. n = 34 (17 panelists × 2 reps). Samples Test 1 Test 2Total Cola + 200 ppm Sucralose + 8 8 16 25 ppm Acesulfame PotassiumCola + 100 ppm Sucralose + 9 9 18 12 ppm 4-amino-5,6-dimethylthieno[2,3- d]pyrimidine-2(1H)-one hydrochloride Total 17 17 34Cola + 200 ppm Sucralose >0.791 >0.791 0.864 selected (p-value)

Example 8

Strawberry Flavored Water

Strawberry flavored beverage was prepared using the followingingredients and evaluated for sweetness and/or lingering taste.Composition (k) comprising 50% sucralose and 6.8 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride hadapproximately the same sweetness as composition (j) which comprised 100%sucralose.

TABLE XIII Sample weight (grams) Sample weight (grams) 100% sucralose50% sucralose strawberry strawberry flavored flavored water Ingredientswater (j) (k) Nutriose FB 06 wheat 2.3800 2.3800 dextrine-soluble fiberMalic Acid 0.0450 0.0450 Strawberry flavor 0.3000 0.3000 Sucralose0.0100 0.0050 Water 97.1558 97.1620 Ace K 0.0012 0.0000 Propylene glycol0.0680 0.0000 Salt 0.0400 0.0400 Compound A (1% in 0.0000 0.0680Propylene Glycol) (6.8 ppm neat) Total Weight 100.0000 100.004-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one will beapproximately 20.4 ppm as consumed (12 oz beverage).Human Taste Test:

Flavored Water+Sucralose=water, fiber, strawberry flavor, citric acid,sucralose, acesulfame K. A triangle test with Flavored water(strawberry) control in 100 ppm sucralose with 12 ppm AceK vs. Flavoredwater (strawberry) in 50 ppm sucralose with (29.35 μM) 6.8 ppm COMPOUNDA. Panelists evaluate two flavored water sweet solutions in a triangletaste test procedure. They are given three samples, two of which containthe same solution, and are instructed to select the sample that isdifferent. They perform a total of two triangle tests: Flavored water(strawberry) control in 100 ppm sucralose with 12 ppm AceK vs. Flavoredwater (strawberry) in 50 ppm sucralose with (29.35 μM) 6.8 ppm COMPOUNDA.

Conclusions:

Panelists were unable to perceive a significant difference betweenFlavored water (strawberry) control in 100 ppm sucralose with 12 ppmAceK vs. Flavored water (strawberry) in 50 ppm sucralose with (29.35 μM)6.8 ppm COMPOUND A.

Two panelists correctly identified the different sample in both triangletests.

Of the panelists who correctly identified the different sample, mostindicated that it was difficult to discriminate the different sample.The removal of Acesulfame Potassium also reduces or eliminates thebitter or off taste from the drink.

TABLE XIV Triangle test results for 100 ppm sucralose with 12 ppm AceKvs. Flavored water (strawberry) in 50 ppm sucralose with (29.35 μM) 6.8ppm COMPOUND A. n = 22 (11 panelists × 2 reps). Samples Test 1 Test 2Total Flavored Water + 100 ppm 7 7 14 Sucralose Flavored Water + 50 ppm4 4 8 Sucralose Total 11 11 22 Confidence 0.473 0.473 0.540 Significance0.527 0.527 0.460

Example 9

Vanilla Frozen Dairy Dessert

Vanilla frozen dairy dessert was prepared using the followingingredients and evaluated for sweetness and/or lingering taste.Composition (m) comprising 50% sucralose and 6.6 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride hadapproximately the same sweetness as composition (l) which comprised 100%sucralose.

TABLE XV Sample weight (grams) Sample weight (grams) 100% sucralosevanilla 50% sucralose vanilla frozen dairy dessert frozen dairy dessertIngredients (l) (m) Low fat milk (1%) 78.37025 78.37775 Maltitol powder9.90000 9.90000 Wheat Dextrin 7.50000 7.50000 Whey powder 2.450002.45000 Maltodextrin 1.20000 1.20000 Stabilizer 0.40000 0.40000Sucralose 0.01250 0.00625 Acesulfame Potassium 0.00125 0.00000 Vanillaflavor 0.10000 0.10000 Propylene glycol 0.06600 0.0000 Compound A (1% in0.00000 0.06600 Propylene Glycol) Total Weight 100.00000 100.000004-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one will beapproximately 6.6 ppm as consumed (½ cup vanilla frozen dairy dessert).Human Taste Test:

Two human tasters were used in the taste test. Paired Comparison Testwith a Full Sucralose+AceK vanilla frozen dairy dessert and 50%Sucralose (no AceK)+6.6 ppm (28.49 μM) Compound A vanilla frozen dairydessert. Panelists evaluated 2 frozen dairy desserts in a pairedcomparison taste test procedure. Panelists performed 2 tests each. Theywere instructed to select the sweeter of the two samples. They were alsoasked to comment on how difficult it was to tell the difference insweetness between both samples and if any off tastes were perceived.

Product:

Full Sucralose+AceK vanilla frozen dairy dessert and 50% Sucralose (noAceK)+6.6 ppm (28.49 μM) Compound A vanilla frozen dairy dessert.

Conclusions:

Panelists found 50% Sucralose (no AceK)+6.6 ppm (28.49 μM Compound Avanilla frozen dairy dessert was not significantly different insweetness than Full Sucralose+AceK vanilla frozen dairy dessert(p>0.05). 14 out of 26 tests indicated 50% Sucralose (no AceK)+6.6 ppm(28.49 μM) Compound A vanilla frozen dairy dessert was the sweetersample.

3/13 panelists chose 50% Sucralose (no AceK)+6.6 ppm (28.49 μM) CompoundA vanilla frozen dairy dessert as the sweeter sample in two pairedcomparisons.

8/13 panelists chose 50% Sucralose (no AceK)+6.6 ppm (28.49 μM) CompoundA vanilla frozen dairy dessert as the sweeter sample in one pairedcomparison.

2/13 panelists chose 50% Sucralose (no AceK)+6.6 ppm (28.49 μM) CompoundA vanilla frozen dairy dessert as the sweeter sample in zero pairedcomparisons.

Panelists found the test very difficult and did not detect anyoff-tastes.

The removal of Acesulfame Potassium also reduces or eliminates thebitter or off taste from the dairy frozen dessert.

TABLE XVI Sample selected as more sweet by panelists. n = 26 (13panelists × 2 reps). Samples Total Full Sucralose + AceK Vanilla FrozenDairy 12 Dessert 50% Sucralose (no AceK) + 6.6 ppm (28.49 μM) 14Compound A Vanilla Frozen Dairy Dessert Total 26 50% Sucralose (noAceK) + 6.6 ppm (28.49 μM) 0.845 Compound A Vanilla Frozen Dairy Dessert(p-value)

Example 10

Preparation of Solutions of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one

In edible compositions, above,4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one (or salts,solvates, and/or esters thereof) may be added in a stable, liquiddiluted form because of its potency. This form improves the use of theenhancer in testing or commercial applications. Preparation procedure ofthe liquid diluted form:

-   -   1. Weigh desire amount of compound.    -   2. Calculate the volume of food grade solvent(s) (water, Ethyl        Alcohol, Isopropyl Alcohol, Butylene Glycol, Glycerol, vegetable        oils (soy, corn, peanut, persic, cottonseed, sesame),        fractionated coconut oil, triacetin, tributyrin, mono and        diglycerides, ethyl lactate, ethyl levulinate, butyl stearate,        triethyl citrate, diethyl succinate, diethyl malonate, acetic        acid, lactic acid, benzyl alcohol, tetrahydrofurfural alcohol,        D-limonene, γ-valeralactone, butyrolactone, Tween) to add to the        dry, weighed out compound to make a concentration of        1,000-50,000 ppm (0.1-5%).    -   3. Pre heat the appropriate amount of solvent to 160° F. while        stirring at 1,100 rpm on a hot plate using a stir bar.    -   4. Add pre-weighed compound to heated solvent (when temperature        reaches 160° F.).    -   5. Continue heating solvent and inspect to insure complete        dissolution, return to the hot plate if necessary.    -   In one embodiment, the solution contains 1%        4-amino-5,6-dimethylthieno[2,3-d]pyrimidine -2(1H)-one in        propylene glycol.

Ingredients Percentage Propylene Glycol 99.000004-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one 01.00000hydrochloride Total 100.00000

Example 11

Sweetness Delivery Profile Study

6 panelists evaluated two aqueous sucralose compositions (100 ppmsucralose, 50 ppm sucralose+2.0 ppm4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloride) forsweetness delivery profile. The panelists compared 3 pairs of randomizedsamples, and were asked to pick the samples with a taster onset ofsweetness and reduced linger of sweetness. All of the panelists ratedthe 50 ppm sucralose+2 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloridesolutions to have a shorter linger of sweetness delivery, and 3panelists rated the 50 ppm sucralose+2 ppm of4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-one hydrochloridesolution to have a faster onset of sweetness delivery.

Example 12

Sugar Free Strawberry Yogurt

TABLE XVII Sample weight (grams) Sample weight (grams) 50% sucralose +11 ppm 100% sucralose sugar sugar free Ingredients free strawberryyogurt strawberry yogurt Frozen Strawberries 6.84 6.84 Rezista, Modified0.81 0.81 Food Starch Cellulose Gum 0.018 0.018 Potassium Sorbate 0.0090.009 Sucralose 0.022 (216 ppm) 0.011 (108 ppm) Strawberry Flavor 0.1080.108 Water 10.193 10.19 Plain Fat Free Yogurt 82.00 81.904 Compound A(1% in 0.00 0.11 Propylene Glycol) Total Weight 100.00000 100.00000Human Taste Test:

Paired comparison taste test with Strawberry Yogurt with 216 ppmSucralose vs. Strawberry Yogurt with 108 ppm Sucralose+11 ppm Compound A

Procedure:

Panelists evaluate two yogurt samples in a paired comparison taste testprocedure and are instructed to select the sweeter of the two samples.They perform a total of three paired comparison tests each containingthe following samples: Strawberry Yogurt with 216 ppm Sucralose vs.Strawberry Yogurt with 108 ppm Sucralose+11 ppm Compound A.

Products:

-   -   Strawberry Yogurt=Frozen Strawberry, modified food starch,        cellulose gum, potassium sorbate, sucralose, strawberry flavor,        water, fat-free plain yogurt, heated propylene glycol, optional        Compound A        Conclusions:    -   Panelists found Strawberry Yogurt with 216 ppm Sucralose was not        significantly different in sweetness than Strawberry Yogurt with        108 ppm Sucralose+11 ppm Compound A (p<0.05). 22 of 42 tests        indicated Strawberry Yogurt with 108 ppm Sucralose+11 ppm        Compound A was the sweeter sample.    -   4/14 panelists chose Strawberry Yogurt with 108 ppm Sucralose+11        ppm Compound A as the sweeter sample in all three of the paired        comparison tests. 3/14 panelists chose Strawberry Yogurt with        216 ppm Sucralose as the sweeter sample in all three of the        paired comparison tests.

TABLE XVIII Sample selected as sweeter by panelists: Strawberry Yogurtwith 216 ppm Sucralose vs. Strawberry Yogurt with 108 ppm Sucralose + 11ppm Compound A. n = 42 (14 panelists × 3 reps). Samples Test 1 Test 2Test 3 Total Strawberry Yogurt with 8 4 8 20 216 ppm SucraloseStrawberry Yogurt with 6 10 6 22 108 ppm Sucralose + 11 ppm Compound ATotal 14 14 14 42 Strawberry Yogurt with >0.791 0.180 >0.791 0.878 108ppm Sucralose + 11 ppm Compound A selected (p-value)

Example 13

Synthesis of 2-amino-4,5-dimethylthiophene-3-carbonitrile

A solution of 3-mercapto-2-butanone (1.00 kg, 9.0 mole, 93.6% assay) in2.0 L SDA 3C 200 Proof, absolute Ethanol (Ethanol) is prepared in a 5 L1N RBF fitted with torian and transfer tubing. Malononitrile (588.8 g,8.9 mole) is dissolved in 5.0 L Ethanol and cooled to 4° C. at whichpoint triethylamine (250 mL, 1.8 mole, 0.2 equivalent) is added with a560 mL ethanol rinse. The anionic malononitrile solution is cooled to−2° C. and the 3-mercaptobutanone solution is added over 1.3 hrs at −1to −5° C. After an hour, the reaction shows less than 0.1%malononitrile. The reaction is concentrated on the rotovap (40° C. bath)to a slurry of approximately 2.5 L and 3.0 L of heptanes are added. Theslurry is cooled to 5° C. for 30 minutes and the solids collected byfiltration. The solids are rinsed with 2.5 L of 20% Ethanol in heptanesin 7 portions. The excess solvent is removed on the filter, and the wetcake dried in a vacuum oven overnight at 40° C. and full vacuum to givean off white solid as 2-amino-4,5-dimethylthiophene-3-carbonitrile (870g, 64.1% yield, 99.7% purity shown by HPLC). The filtrates arere-concentrated to an oily slurry which is filtered and rinsed with 0.5L of 20% Ethanol in heptanes. The second crop of solids is driedseparately (47 g, 3.5% yield, 98.6% purity shown by HPLC). ¹H NMR (400MHz, DMSO-d₆) δ 1.93 (d, J=1.2 Hz, 3H), 2.07 (d, J=1.2 Hz, 3H), 3.33 (s,2H). MS 153 (MH⁺). HPLC Retention Time: approximately 10.9 minute(Phenomenex Luna C18 (2) column, acetonitrile/water with 0.1% AcOH).

2-Mercapto-3-butanone can be readily made from 2-butanone, sulfur,ammonia in high yields as described in U.S. Pat. No. 2,888,487, andshown in Scheme 2 below.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” or “and/or” is used as a function word to indicate that twowords or expressions are to be taken together or individually. The terms“comprising”, “having”, “including”, and “containing” are to beconstrued as open-ended terms (i.e., meaning “including, but not limitedto”). The endpoints of all ranges directed to the same component orproperty are inclusive and independently combinable.

While the present invention has been particularly shown and describedwith respect to preferred embodiments thereof, it will be understood bythose skilled in the art that the foregoing and other changes in formsand details may be made without departing from the spirit and scope ofthe invention. It is therefore intended that the present invention notbe limited to the exact forms and details described and illustrated butfall within the scope of the appended claims.

We claim:
 1. A process of preparing a compound having structural Formula(a):

comprising: mixing a compound having structural Formula (b):

with a compound having structural Formula (c):

in the presence of an organic amine at a temperature of about 0° C. orbelow to obtain a reaction mixture; maintaining the reaction mixture ata temperature of about 0° C. or below for about 30 to about 90 minutes;concentrating the reaction mixture to obtain a slurry; and filtering theslurry to obtain the compound having structural Formula (a) as solidparticles; wherein: R¹ is hydrogen, alkyl, heteroalkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl; R² is hydrogen, alkyl,heteroalkyl, alkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;or alternatively, R¹ and R², together with the atoms to which they areattached, form a carbocyclic ring or heterocyclic ring; X is CN or—C(O)R³; R³ is alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR⁴,or N(R⁴⁾ ₂; and each R⁴ is independently hydrogen, alkyl, aryl,heteroaryl, arylalkyl, or heteroarylalkyl.
 2. The process of claim 1,further comprising: washing the solid particles of the compound havingstructural Formula (a) with an eluting solvent, wherein the elutingsolvent is a mixture of an alcohol solvent and an alkane hydrocarbonsolvent.
 3. The process of claim 1, wherein the volume ratio of thealcohol solvent to the alkane hydrocarbon solvent is from about 1:9 toabout 1:3.
 4. The process of claim 1, wherein the mixing step comprises:adding an alcohol solution of the compound having structural Formula (b)to an alcohol solution of the compound having structural Formula (c) andthe organic amine at a temperature of about 0° C. or below.
 5. Theprocess of claim 1, wherein the molar ratio of the compound havingstructural formula (b) to the compound having structural formula (c) isfrom about 1:0.9 to about 1:1.1.
 6. The process of claim 1, wherein themolar ratio of the compound having structural formula (c) to the organicamine is from about 5.1:1 to about 4.9:1.
 7. The process of claim 1,wherein R¹ is hydrogen or alkyl; R² is hydrogen or alkyl; and X is CN.8. The process of claim 1, wherein R¹ is methyl; R² is methyl; and X isCN.